Cleidocranial dysostosis (CCD), also called cleidocranial dysplasia, is a

birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...

that mostly affects the

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s and

teeth A tooth ( : teeth) is a hard, calcified structure found in the jaws (or mouths) of many vertebrates and used to break down food. Some animals, particularly carnivores and omnivores, also use teeth to help with capturing or wounding prey, ...

. The collarbones are typically either poorly developed or absent, which allows the shoulders to be brought close together. The front of the

skull The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, th ...

often does not close until later, and those affected are often shorter than average. Other symptoms may include a prominent forehead, wide set eyes, abnormal teeth, and a flat nose. Symptoms vary among people; however, intelligence is typically unaffected. The condition is either inherited from a person's parents or occurs as a new

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

. It is inherited in an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner. It is due to a defect in the

RUNX2 Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...

gene which is involved in bone formation. Diagnosis is suspected based on symptoms and

X-rays An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nbs ...

with confirmation by

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

. Other conditions that can produce similar symptoms include mandibuloacral dysplasia,

pyknodysostosis Pycnodysostosis (from Greek: πυκνός (puknos) meaning "dense", ''dys'' ("defective"), and ''ostosis'' ("condition of the bone")), is a lysosomal storage disease of the bone caused by a mutation in the gene that codes the enzyme cathepsin K. ...

osteogenesis imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be ...

, and Hajdu-Cheney syndrome. Treatment includes supportive measures such as a device to protect the skull and dental care. Surgery may be performed to fix certain bone abnormalities. Life expectancy is generally normal. It affects about one per million people. Males and females are equally commonly affected. Modern descriptions of the condition date to at least 1896. The term is from ''cleido'' meaning collarbone, ''cranial'' from the Greek κρανιὀς meaning skull, and ''dysostosis'' meaning formation of abnormal bone.

Signs and symptoms

Cleidocranial dysostosis is a general skeletal condition so named from the collarbone (cleido-) and

cranium The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, th ...

deformities which people with it often have. People with the condition usually present with a painless swelling in the area of the clavicles at 2–3 years of age. Common features are: *

Clavicle The clavicle, or collarbone, is a slender, S-shaped long bone approximately 6 inches (15 cm) long that serves as a strut between the shoulder blade and the sternum (breastbone). There are two clavicles, one on the left and one on the r ...

s (collarbones) can be partly missing leaving only the medial part of the bone. In 10% of cases, they are completely missing. If the collarbones are completely missing or reduced to small vestiges, this allows hypermobility of the shoulders including ability to touch the shoulders together in front of the chest. The defect is bilateral 80% of the time. Partial collarbones may cause nerve damage symptoms and therefore have to be removed by surgery. * The mandible is

prognathic Prognathism, also called Habsburg jaw or Habsburgs' jaw primarily in the context of its prevalence amongst members of the House of Habsburg, is a positional relationship of the mandible or maxilla to the skeletal base where either of the jaws pr ...

due to hypoplasia of maxilla ( micrognathism) and other facial bones. * A soft spot or larger soft area in the top of the head where the fontanelle failed to close, or the fontanelle closes late. * Bones and joints are underdeveloped. People are shorter and their frames are smaller than their siblings who do not have the condition. * The

permanent teeth Permanent teeth or adult teeth are the second set of teeth formed in diphyodont mammals. In humans and old world simians, there are thirty-two permanent teeth, consisting of six maxillary and six mandibular molars, four maxillary and four mand ...

include supernumerary teeth. Unless these supernumeraries are removed they will crowd the adult teeth in what already may be an underdeveloped jaw. If so, the supernumeraries will probably need to be removed to make space for the adult teeth. Up to 13 supernumerary teeth have been observed. Teeth may also be displaced. Cementum formation may be deficient. * Failure of eruption of

. * Bossing (bulging) of the

forehead In human anatomy, the forehead is an area of the head bounded by three features, two of the skull and one of the scalp. The top of the forehead is marked by the hairline, the edge of the area where hair on the scalp grows. The bottom of the fo ...

. * Open skull sutures, large fontanelles. * Hypertelorism. * Delayed

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in ...

of bones forming

symphysis pubis The pubic symphysis is a secondary cartilaginous joint between the left and right superior rami of the pubis of the hip bones. It is in front of and below the urinary bladder. In males, the suspensory ligament of the penis attaches to the pubic ...

, producing a widened symphysis. *

Coxa vara Coxa vara is a deformity of the hip, whereby the angle between the head and the shaft of the femur is reduced to less than 120 degrees. This results in the leg being shortened and the development of a limp. It may be congenital and is commonly cau ...

can occur, limiting

abduction Abduction may refer to: Media Film and television * "Abduction" (''The Outer Limits''), a 2001 television episode * " Abduction" (''Death Note'') a Japanese animation television series * " Abductions" (''Totally Spies!''), a 2002 episode of an ...

and causing Trendelenburg gait. * Short middle fifth

phalanges The phalanges (singular: ''phalanx'' ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones. ...

, sometimes causing short and wide fingers. * Vertebral abnormalities. * On rare occasions, brachial plexus irritation can occur. *

Scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not ty ...

, spina bifida and syringomyelia have also been described. Other features are: parietal bossing, basilar invagination ( atlantoaxial impaction), persistent

metopic suture The frontal suture is a fibrous joint that divides the two halves of the frontal bone of the skull in infants and children. Typically, it completely fuses between three and nine months of age, with the two halves of the frontal bone being fused t ...

, abnormal ear structures with

hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken l ...

, supernumerary ribs, hemivertebrae with spondylosis, small and high scapulae,

hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.illiac bones, absence of the pubic bone, short / absent fibular bones, short / absent radial bones, hypoplastic terminal

Genetics

CCD is usually

, but in some cases its cause is not known. The main mechanism is thought to involve haploinsufficiency caused by mutations in

CBFA1 Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...

(also known as Runx2), a

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

located on the short arm of

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...

( 6p21), which encodes a transcription factor required for the differentiation of stem cells into

osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

s. This results in delayed ossification of midline structures of the body and ensuing defects in membranous and endochondral bone formation.

Diagnosis

Different features of the dysostosis are significant. Radiological imaging helps confirm the diagnosis. During gestation (pregnancy), clavicular size can be calculated using available nomograms. Wormian bones can sometimes be observed in the skull. Diagnosis of CCD spectrum disorder is established in an individual with typical clinical and radiographic findings and/or by the identification of a heterozygous pathogenic variant in RUNX2 (CBFA1).

Treatment

Around 5 years of age, surgical correction may be necessary to prevent any worsening of the deformity. If the mother has dysplasia, caesarian delivery may be necessary. Craniofacial surgery may be necessary to correct skull defects. Coxa vara is treated by corrective femoral osteotomies. If there is brachial plexus irritation with pain and numbness, excision of the clavicular fragments can be performed to decompress it. In case of open fontanelle, appropriate headgear may be advised by the orthopedist for protection from injury.

Prognosis

Several studies have reported that life expectancy appears to be normal for people with CCD.

Epidemiology

Cleidocranial dysostosis affects about one per million people.

Notable cases

In 1987, a young girl named Jessica McClure fell down a narrow well pipe in her family's Texas property. Ron Short, a roofing contractor who was born without collarbones because of cleidocranial dysostosis and thus could collapse his shoulders to work in cramped corners, arrived at the site and offered to go down the shaft. The rescuers did not end up using him, though McClure was successfully recovered from the well. Actor Gaten Matarazzo was born with cleidocranial dysplasia, which is incorporated into his character Dustin Henderson's storyline on ''

Stranger Things ''Stranger Things'' is an American science fiction horror drama television series created by the Duffer Brothers, who also serve as showrunners and are executive producers along with Shawn Levy and Dan Cohen. Produced by Monkey Massacre Pr ...

''. Sibling actress-singers Milly and Abby Shapiro were born with cleidocranial dysplasia, a trait they share with their mother.

References

External links

* {{Transcription factor deficiencies Congenital disorders of musculoskeletal system Transcription factor deficiencies Rare diseases Wikipedia medicine articles ready to translate